RESUMEN
Agomelatine is a selective agonist of melatonin receptor 1A/melatonin receptor 1B (MT1/MT2) and antagonist of 5-hydroxytryptamine 2C receptors. It is used clinically to treat major depressive episodes in adults. The pro-chronobiological activity of agomelatine reconstructs sleep-wake rhythms and normalizes circadian disturbances via its agonistic effect of melatonin receptor 1A/melatonin receptor 1B, which work simultaneously to counteract depression and anxiety disorder. Moreover, by antagonizing neocortical postsynaptic 5-hydroxytryptamine 2C receptors, agomelatine enhances the release of dopamine and noradrenaline in the prefrontal cortex, increases the activity of dopamine and noradrenaline, and thereby reduces depression and anxiety disorder. The combination of these two effects means that agomelatine exhibits a unique pharmacological role in the treatment of depression, anxiety, and disturbance of the circadian rhythm. Emotion and sleep are closely related to memory and cognitive function. Memory disorder is defined as any forms of memory abnormality, which is typically evident in a broad range of neurodegenerative diseases, including Alzheimer's disease. Memory impairment and cognitive impairment are common symptoms of neurodegenerative and psychiatric diseases. Therefore, whether agomelatine can improve memory and cognitive behaviors if used for alleviating depression and circadian-rhythm sleep disorders has become a research "hotspot". This review presents the latest findings on the effects of agomelatine in the treatment of psychologic and circadian-rhythm sleep disorders in clinical trials and animal experiments. Our review evaluates recent studies on treatment of memory impairment and cognitive impairment in neurodegenerative and psychiatric diseases.
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Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive decline, which could be promoted by mitochondrial dysfunction induced by mitochondrial Ca 2+ (mCa 2+) homeostasis Mitochondrial calcium uniporter (MCU), a key channel of mCa 2+ uptake, may be a target for AD treatment. In the present study, we reveal for the first time that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through radial arm maze task. Western blot analysis, transmission electron microscopy (TEM), Golgi staining, immunohistochemistry (IHC) and ELISA results demonstrate that MCU knockdown in hippocampal neurons upregulates the levels of postsynaptic density protein 95 (PSD95) and synaptophysin (SYP), and increases the numbers of synapses and dendritic spines. Meanwhile, MCU knockdown in hippocampal neurons decreases the neuroinflammatory response induced by astrogliosis and high levels of IL-1ß and TNF-α, and improves the PINK1-Parkin mitophagy signaling pathway and increases the level of Beclin-1 but decreases the level of P62. In addition, MCU knockdown in hippocampal neurons recovers the average volume and number of mitochondria. These data confirm that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through ameliorating the synapse structure and function, relieving the inflammation response and recovering mitophagy, indicating that MCU inhibition has the potential to be developed as a novel therapy for AD.
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Enfermedad de Alzheimer , Canales de Calcio , Memoria , Neuronas , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Ratones Transgénicos , Neuronas/metabolismo , Canales de Calcio/genéticaRESUMEN
Autophagy is a major intracellular degradation pathway for the clearance of damaged organelles and misfolded peptides. Previous studies have indicated that autophagy is involved in the pathogenesis of neurodegenerative disease including Alzheimer's disease (AD). Defective autophagy and highly expressed ubiquitin-conjugating enzyme 2 C (Ube2c) have been found in AD patients and mouse. However, little is known about the regulation of autophagy in AD. The association of Ube2c with autophagy, amyloid pathology and cognitive deficits in AD remains unclear. In the present study, we characterized over expression of Ube2c and declined autophagy in amyloid ß (Aß)-treated microglia and demonstrated the protective effects of agomelatine (AGO) in APP/PS1 mice. We found that knockdown of Ube2c with AAV2 encoding shUbe2c resulted in an obvious enhancement of autophagy in BV2 microglia cells, and an alleviation of Aß pathology and memory deficits in APP/PS1 mice. Further, pharmacological inhibition of Ube2c by AGO significantly reduced Aß plaques, improved synaptic plasticity and cognitive behaviors in APP/PS1 mice, as well as promoted autophagy in microglia. Our findings uncover a potent role of Ube2c over-expression and autophagy decline in the pathogenesis of AD, and suggest that regulation of Ube2c and autophagy may provide an important clue and a potential target for the novel therapeutics of AD.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enzimas Ubiquitina-Conjugadoras/farmacocinética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/complicaciones , Placa Amiloide/complicaciones , Placa Amiloide/tratamiento farmacológicoRESUMEN
In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aß1-42-induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer's disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer's disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer's disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer's disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.
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Ti-6.5Al-2Zr-1Mo-1V (TA15), widely used in the aerospace industry, is a medium- to high-strength, near-α titanium alloy with high aluminium equivalent value. The TA15 fabricated via laser powder bed fusion (L-PBF) normally presents a typical brittle appearance in as-built status, with high strength and low ductility. In this study, the microstructure and properties of L-PBF TA15 were engineered by various heat treatments below the ß-transus temperature (1022 °C). After heat treatment, the original acicular martensite gradually transforms into a typical lamellar α + ß dual-phase structure. Withannealing temperature increases, the lamellar α phase thickened with a decreased aspect ratio. Globularisation of the α grain can be noticed when annealing above 800 °C, which leads to a balance between strength and ductility. After heat treatment between 800-900 °C, the desired combination of strength and ductility can be achieved, with elongation of about 12.5% and ultimate tensile strength of about 1100 Mpa.
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BACKGROUND: Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-ß protein (Aß) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. OBJECTIVE: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. METHODS: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. RESULTS: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1ß, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. CONCLUSION: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.
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Adiponectina/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/patología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Memoria Espacial/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacosRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. OBJECTIVE: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. METHODS: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. RESULTS: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. CONCLUSION: DA4-JC is a promising drug for the treatment of AD.
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Enfermedad de Alzheimer/patología , Disfunción Cognitiva/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Homólogo 4 de la Proteína Discs Large/genética , Péptido 1 Similar al Glucagón/agonistas , Potenciación a Largo Plazo/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Sinapsis/metabolismoRESUMEN
Sleep exerts important functions in the regulation of cognition and emotion. Recent studies have found that sleep disorder is one of the important risk factors for Alzheimer's disease (AD), but the effects of chronic sleep deprivation on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1/tau triple transgenic AD model (3xTg-AD) mice and wild type (WT) mice (n = 8 for each group) were subjected to chronic sleep deprivation by using the modified multiple platform method, with 20 h of sleep deprivation each day for 21 days. Then, open field test, elevated plus maze test, sugar water preference test, object recognition test, Y maze test and conditioned fear memory test were performed to evaluate anxiety- and depression-like behaviors, and multiple cognitive functions. In addition, the immunohistochemistry technique was used to observe pathological characteristics in the hippocampus of mice. The results showed that: (1) Chronic sleep deprivation did not affect anxiety- (P = 0.539) and depression-like behaviors (P = 0.874) in 3xTg-AD mice; (2) Chronic sleep deprivation exacerbated the impairments of object recognition memory (P < 0.001), working memory (P = 0.002) and the conditioned fear memory (P = 0.039) in 3xTg-AD mice; (3) Chronic sleep deprivation increased amyloid ß (Aß) deposition (P < 0.001) and microglial activation (P < 0.001) in the hippocampus of 3xTg-AD mice, without inducing abnormal tau phosphorylation and neurofibrillary tangles. These results indicate that chronic sleep deprivation exacerbates the impairments of recognition memory, working memory and conditioned fear memory in 3xTg-AD mice by aggravating Aß deposition and the excessive activation of microglia in the hippocampus.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animales , Cognición , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1 , Privación de Sueño , Proteínas tauRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits. Sleep deprivation (SD) could lead to memory deficits, and it was a candidate risk factor for AD. However, the effects of chronic SD on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1 transgenic mice and wild type (WT) littermates were subjected to chronic SD by using the modified multiple platform method (MMPM), with 20 h of SD each day for 21 days. Then, the effects of chronic SD on cognitive functions in APP/PS1 mice were tested by using behavioral tests, the potential mechanisms were investigated by in vivo electrophysiological recording, western blot and immunochemistry. The results showed that chronic SD obviously aggravated the cognitive impairments, exacerbated in vivo hippocampal long-term potentiation (LTP) suppression, reduced the expression level of PSD95, increased amyloid-ß (Aß) protein deposition and overactivated microglia in the hippocampus of APP/PS1 mice. These results indicate that chronic SD exacerbates the cognitive deficits in APP/PS1 mice by accelerating the development of AD pathologies, reducing the expression of PSD95 and aggravating the LTP suppression in hippocampus. At the same time, chronic SD also impaired cognitive functions and synaptic plasticity in WT mice through down-regulating the level of PSD95 and activating microglia. These findings further clarify the electrophysiological and molecular mechanisms of exacerbated cognitive deficits in AD caused by chronic SD.
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Cognición/fisiología , Plasticidad Neuronal/fisiología , Privación de Sueño/fisiopatología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Trastornos del Conocimiento/etiología , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/patología , Ratones , Ratones Transgénicos , Placa Amiloide/patología , Presenilina-1/genética , Presenilina-1/metabolismo , Sueño/fisiologíaRESUMEN
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. OBJECTIVE: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. METHODS: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aß plaques and neuroinflammation in the brain. IL-1ß, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. RESULTS: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aß deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1ß and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. CONCLUSION: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.
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Disfunción Cognitiva/tratamiento farmacológico , Polipéptido Inhibidor Gástrico/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Cognición/efectos de los fármacos , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratones , Ratones Transgénicos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/patología , Placa Amiloide/patologíaRESUMEN
BACKGROUND: Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. METHODS: Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. RESULTS: TSA treatment not only reduced amyloid ß (Aß) plaques and soluble Aß oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aß pathology by TSA was attributed to the enhancement of Aß clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aß aggregation and promoted the phagocytosis of Aß oligomers. CONCLUSIONS: These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
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Enfermedad de Alzheimer , Anciano , Albúminas , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animales , Cromatografía Liquida , Cognición , Modelos Animales de Enfermedad , Células Endoteliales , Humanos , Ácidos Hidroxámicos , Ratones , Ratones Transgénicos , Presenilina-1/genética , Espectrometría de Masas en TándemRESUMEN
Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Azepinas/farmacología , Azepinas/uso terapéutico , Trastornos Cronobiológicos/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Neuroprostanos , Antagonistas de los Receptores de Orexina , Triazoles/farmacología , Triazoles/uso terapéutico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Trastornos Cronobiológicos/etiología , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatología , Potenciación a Largo Plazo/efectos de los fármacos , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Orexinas/líquido cefalorraquídeoRESUMEN
Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health and cannot be stopped by current treatments. Type 2 diabetes mellitus (T2DM) is a risk factor for AD. Our recent studies reported the neuroprotective effects of a GLP-1/GIP/Glucagon receptor triagonist (Triagonist), a novel unimolecular anti-diabetic drug, in cognitive and pathological improvements of 3xTg-AD mice. However, the detailed electrophysiological and molecular mechanisms underlying neuroprotection remain unexplored. The present study investigated the underlying electrophysiological and molecular mechanisms further by using whole-cell patch clamp techniques. Our results revealed that chronic Triagonist treatment effectively reduced working memory and reference memory errors of 3xTg-AD mice in a radial maze test. In addition, the Triagonist increased spontaneous excitatory synaptic activities, differentially modulated voltage- and chemically-gated Ca2+ flux, and reduced the over-excitation of pyramidal neurons in hippocampal slices of 3xTg-AD mice. In addition, chronic Triagonist treatment also up-regulated the expression levels of synaptophysin and PSD-95 in the hippocampus of 3xTg-AD mice. These results indicate that the Triagonist could improve memory formation, as well as synaptic transmission, Ca2+ balance, and neuronal excitability in 3xTg-AD mice. These neuroprotective effects of Triagonist may be involved in the up-regulation of synaptophysin and PSD-95. Therefore, the study suggests that multi-receptor agonists might be a novel therapeutic strategy for the treatment of AD.
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Señalización del Calcio/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Memoria a Corto Plazo/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Glucagón/agonistas , Transmisión Sináptica/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Animales , Señalización del Calcio/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Receptor del Péptido 1 Similar al Glucagón/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Hipoglucemiantes/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Técnicas de Cultivo de Órganos , Presenilina-1/genética , Receptores de la Hormona Gastrointestinal/fisiología , Receptores de Glucagón/fisiología , Transmisión Sináptica/fisiología , Proteínas tau/genéticaRESUMEN
Memory deficits with aging are related to the neurodegeneration in the brain, including a reduction in arginine vasopressin (AVP) in the brain of patients with Alzheimer's disease (AD). AVP(4-8), different from its precursor AVP, plays memory enhancement roles in the CNS without peripheral side-effects. However, it is not clear whether AVP(4-8) can improve cognitive behaviors and synaptic plasticity in the APP/PS1 mouse model of AD. Here, we investigated for the first time the neuroprotective effects of AVP(4-8) on memory behaviors and in vivo long-term potentiation (LTP) in APP/PS1-AD mice. The results showed that: (1) APP/PS1-AD mice had lower spontaneous alternation in the Y-maze than wild-type (WT) mice, and this was significantly reversed by AVP(4-8); (2) the prolonged escape latency of APP/PS1-AD mice in the Morris water maze was significantly decreased by AVP(4-8), and the decreased swimming time in target quadrant recovered significantly after AVP(4-8) treatment; (3) in vivo hippocampal LTP induced by high-frequency stimulation had a significant deficit in the AD mice, and this was partly rescued by AVP(4-8); (4) AVP(4-8) significantly up-regulated the expression levels of postsynaptic density 95 (PSD95) and nerve growth factor (NGF) in the hippocampus of AD mice. These results reveal the beneficial effects of AVP(4-8) in APP/PS1-AD mice, showing that the intranasal administration of AVP(4-8) effectively improved the working memory and long-term spatial memory of APP/PS1-AD mice, which may be associated with the elevation of PSD95 and NGF levels in the brain and the maintenance of hippocampal synaptic plasticity.
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Enfermedad de Alzheimer/tratamiento farmacológico , Arginina Vasopresina/análogos & derivados , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/farmacología , Animales , Arginina Vasopresina/administración & dosificación , Arginina Vasopresina/farmacología , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Transgénicos , Fármacos Neuroprotectores/administración & dosificación , Fragmentos de Péptidos/administración & dosificaciónRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aß1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aß plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3ß levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aß and normalization of PI3K/AKT/GSK3ß cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptido 1 Similar al Glucagón/agonistas , Plasticidad Neuronal/efectos de los fármacos , Oxintomodulina/farmacología , Receptores de Glucagón/agonistas , Memoria Espacial/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Modelos Animales de Enfermedad , Péptido 1 Similar al Glucagón/farmacología , Hipocampo/efectos de los fármacos , Insulina/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fármacos Neuroprotectores/farmacología , Oxintomodulina/uso terapéutico , Presenilina-1/genéticaRESUMEN
Cognitive decline, memory impairment and circadian rhythm disturbance are iconic manifestations of Alzheimer's disease (AD). APPswe/PS1dE9 (APP/PS1) mice, a model of AD, show deficits in multiple learning and memory abilities, synaptic plasticity, and behavioral circadian rhythm, but whether circadian differences in cognitive performance and synaptic plasticity could be affected in AD remain unclear. Here, the cognitive behaviors of 6-month-old APP/PS1 mice were assessed by multiple behavior tests in the rest phase (light period) or active phase (dark period) of the day. The possible electrophysiological mechanism was subsequently investigated by in vivo hippocampal long-term potentiation (LTP) recording, and the locomotor activity rhythm of the mice was detected using wheel-running activities. Compared to wild-type (WT) mice, APP/PS1 mice exhibited long-term spatial memory impairment and in vivo hippocampal LTP suppression. In addition, in APP/PS1 mice, circadian differences in new object recognition memory and LTP were lost, and the circadian difference in long-term spatial memory was decreased, accompanied by a less robust locomotor activity rhythm. These results indicate that the loss of circadian differences in new object recognition memory and the decrease in the circadian difference in long-term spatial memory in APP/PS1 mice, which are closely associated with the loss of the circadian difference in LTP and less robust locomotor activity, might occur early in the course of AD.
Asunto(s)
Precursor de Proteína beta-Amiloide , Ritmo Circadiano/fisiología , Disfunción Cognitiva/metabolismo , Aprendizaje por Laberinto/fisiología , Plasticidad Neuronal/fisiología , Presenilina-1 , Precursor de Proteína beta-Amiloide/genética , Animales , Cognición/fisiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
Exaggerated Ca2+ signaling might be one of primary causes of neural dysfunction in Alzheimer's disease (AD). And the intracellular Ca2+ overload has been closely associated with amyloid-ß (Aß)-induced endoplasmic reticulum (ER) stress and memory impairments in AD. Here we showed for the first time the neuroprotective effects of Xestospongin C (XeC), a reversible IP3 receptor antagonist, on the cognitive behaviors and pathology of APP/PS1 AD mice. Male APP/PS1-AD mice (nâ=â20) were injected intracerebroventricularly with XeC (3µmol) via Alzet osmotic pumps for four weeks, followed by cognition tests, Aß plaque examination, and ER stress-related protein measurement. The results showed that XeC pretreatment significantly improved the cognitive behavior of APP/PS1-AD mice, raising the spontaneous alteration accuracy in Y maze, decreasing the escape latency and increasing the target quadrant swimming time in Morris water maze; XeC pretreatment also reduced the number of Aß plaques and the overexpression of ER stress proteins 78 kDa glucose-regulated protein (GRP-78), caspase-12, and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) in the hippocampus of APP/PS1 mice. In addition, in vitro experiments showed that XeC effectively ameliorated Aß1 - 42-induced early neuronal apoptosis and intracellular Ca2+ overload in the primary hippocampal neurons. Taken together, IP3R-mediated Ca2+ disorder plays a key role in the cognitive deficits and pathological damages in AD mice. By targeting the IP3âR, XeC might be considered as a novel therapeutic strategy in AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Cognición/efectos de los fármacos , Hipocampo/efectos de los fármacos , Compuestos Macrocíclicos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Nootrópicos/uso terapéutico , Oxazoles/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Modelos Animales de Enfermedad , Hipocampo/patología , Compuestos Macrocíclicos/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Nootrópicos/farmacología , Oxazoles/farmacología , Placa Amiloide/genética , Placa Amiloide/patologíaRESUMEN
APP/PS1/tau triple transgenic (3xTg) mouse is a classical animal model of Alzheimer's disease (AD), which has abnormalities in recognition and electrophysiological properties at early 6-month-old age. However, few studies were performed by using simultaneously recording cognitive behavior and brain electrical activity in the conscious 3xTg mice. By using a new wireless recording system, we recorded hippocampal Theta oscillations in 3xTg mice during the process of fear conditioning test. The results showed that: (1) in training session, no significant difference in the fear behavior and hippocampal Theta activity was found between 3xTg mice and WT mice; (2) in test session, 3xTg mice showed a significant decrease in freezing ratio compared with WT mice when they were exposed to conditioning stimulus (CS); (3) the 3xTg mice showed lower peak power in Theta oscillation in both Pre-CS and CS duration compared with WT mice; (4) CS effectively induced an increase in the peak frequency of Theta oscillation in WT mice, but not in 3xTg mice. These results indicated that the impairment of cognition behavior in 3xTg mice was accompanied with the decreased peak power and peak frequency of Theta oscillation in the hippocampus, suggesting that a decline in Theta oscillation might be involved in the impairments of the fear conditioning, and the enhanced hippocampal Theta oscillation may be beneficial for improving AD cognitive function.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Condicionamiento Clásico , Miedo , Ritmo Teta , Tecnología Inalámbrica , Animales , Cognición , Modelos Animales de Enfermedad , Hipocampo/fisiopatología , Ratones , Ratones TransgénicosRESUMEN
Amyloid-ß (Aß) peptide and α-synuclein (α-syn) are major components of senile plaques in Alzheimer's disease (AD) and Lewy bodies in Parkinson's disease (PD), respectively. Co-occurrence of Aß and α-syn in the senile brains of AD and LB diseases suggests interactions between the two proteins. However, the significance of the overlapping deposition, especially the effects of α-syn on the Aß aggregation, still remains to be clarified. In the present study, we investigated the effects of α-syn pre-formed fibrils (PFFs) injection on the cognitive behaviors and Aß deposition in the brain of APP/PS1 transgenic AD mice by using Morris water maze (MWM) test, immunohistochemistry and western blot techniques. We found that APP/PS1 transgenic mice exhibited an obvious elevation in the α-syn load, as well as Aß deposition in the brain compared with wild type of C57 BL littermates. 5 months after cerebral injection of exogenous α-syn, MWM tests showed an alleviation in cognitive impairments in APP/PS1 mice; western blot and immunohistochemistry experiments also exhibited a significant reduction in Aß level in the brain of APP/PS1 mice injected with α-syn. These results suggest that α-syn aggregated in the brain of AD may act as a protective factor and defend the brain tissue from early Aß deposition and cognitive deficits.